Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency (ADSL)

October 10, 2022 updated by: Assistance Publique - Hôpitaux de Paris

Evaluation of a Treatment With Allopurinol on Autistic Disorders and Epilepsy in Adenylosuccinate Lyase Deficiency (ADSL)

The aim of this study is to evaluate the effectiveness of allopurinol treatment at 12 months on the adaptive and cognitive functioning of patients with adenylosuccinate lyase deficiency (ADSL). The psychiatric evaluation will involve the use of standardized tools prior to initiation of treatment, and will be repeated 6 months and 12 months after the start of treatment.

The decrease in the concentration of SAICAR and S-Ado metabolites, which are markers of adenylosuccinate lyase (ADSL) deficiency, will also be quantified.

Similarly, the efficacy of allopurinol on epileptic seizures for epileptic patients and on electrocardiogram abnormalities will be evaluated secondarily

Study Overview

Status

Completed

Intervention / Treatment

Detailed Description

Adenylosuccinate lyase deficiency (ADSL) is a rare disorder of purine metabolism whose symptoms are mental retardation, autistic disorders, epilepsy, related to the accumulation of succinylpurines: succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S- Ado). The S-Ado / SAICAr ratio in the cerebrospinal fluid (CSF) is correlated with the clinical severity: the cerebral toxicity of SAICAr is incriminated. There is no specific treatment.

Based on the work of Gertrude B. Elion (1988 Nobel Prize in Medicine), who reports that allopurinol (a structural analogue of hypoxanthine) can be a substrate for hypoxanthine phosphoribosyltransferase (HPRT) and thus produce allopurinol ribonucleotides with as a first step in the de novo synthesis of purines, investigators tested the hypothesis that treatment with allopurinol in children with ADSL deficiency would reduce the production of the toxic metabolite SAICAr.

This hypothesis was validated in 3 minor patients with biological and clinical improvement.

So the investigators put the phase II, non-comparative study based on 4 visits to Necker-Enfants malades Hospital or La Pitié-Salpêtrière Hospital: Month 0 (before treatment), Month 3, Month 6 and Month 12 after the start of treatment.

After verification of the inclusion criteria and information of the parents or the patient or guardian, signature of the consent and inclusion of the patient:

  • Clinical and neurological evaluation;
  • Psychiatric assessment with standardized tests;
  • Biological evaluation: determination of urinary and plasma metabolites (SAICAr, S-Ado, ...) Experimental treatment: Allopurinol (Zyloric®) will be administered orally for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure.

Study Type

Interventional

Enrollment (Actual)

8

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Paris, France, 75013
        • LA PITIE-SALPETRIERE Hospital, AP-HP
      • Paris, France, 75015
        • Department of Pediatry. Reference centre of Hereditary diseases of the metabolism of child and adult. Necker - Enfants malades Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Child (minimum age 18 months) or adult with adenylosuccinate lyase; deficiency (ADSL) confirmed by quantification of SAICAr and S-Ado urinary;
  • Girls / women of childbearing age must:

    • have a negative pregnancy test;
    • agree to use a reliable method of contraception from the baseline visit to the last dose of study treatment
  • Consent of the patient, his parents or his legal representative;
  • Beneficiary of social security (affiliated or entitled).

Exclusion Criteria:

  • Refusal of the child, his parents or the patient or his representative;
  • Allergy known to allopurinol or to one of the constituents of the product (lactose in particular);
  • Patients treated with Antipurines (azathioprine, mercaptopurine);
  • Patients treated with vidarabine, cytotoxic drugs (eg cyclophosphamide, doxorubicin, bleomycin, procarbazine, alkyl halides), ciclosporin, or didanosine
  • Renal failure characterized by creatinine clearance <80 ml/mn
  • Hepatic insufficiency
  • Medullary insufficiency but possibly serious
  • Breastfeeding
  • Pregnancy or wishing to conceive during the study period

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Allopurinol
Oral administration of Allopurinol (Zyloric®) for 12 months without exceeding 400 mg / day in children and 900 mg / day in adults, with dosage adjustment in case of renal failure
Daily oral administration
Other Names:
  • Zyloric®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of adaptive functional improvement : composite total score for Vineland II adaptive behaviour Scale
Time Frame: 12 months

to assess Efficacy of Allopurinol (Zyloric)® treatment from Baseline : For each scale : Mean : 100 SD : 15

  • Adaptive behaviour composite : Range 20 to 180 -Domains scores : Range 20 to 140 -Communication : Range 20 to 140 -Daily living skills : Range 20 to 140 -Socialization : 20 to 140 -Motor skills : 20 to 140 For each scale values are considered to be better or worse outcome :High 130 to 140 -Moderately High 115 to 129 -Adequate 86 to 114 -Moderately Low 71 to 85 -Low 20 to 70 Total score is obtained by summing the subdomains scores
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evolution of the Scores of different subdomains Vineland II scale from baseline
Time Frame: at 0, 6 months and 12 months
Clinical evolution for developmental and cognitive assessment
at 0, 6 months and 12 months
Evolution of the Psycho-Educative Profile (PEP III/R) from baseline
Time Frame: at 0, 12 months
Clinical evolution for developmental and cognitive assessment
at 0, 12 months
Evolution of the Score ADI-R (Autism Diagnostic Interview-Revised) from baseline
Time Frame: at 0, 12 months

Clinical evaluation for autistic symptoms : scale ranges :

  • A : Social interactions: 0 to 30 (significative if >10)
  • B : Communication : 0 to 26 (significative if > 7 or 8)
  • C : Repetitive and restricted interests : 0 to 16 (significative if >3)
  • D : Developmental abnormality present before 36 months : 0 to 5 (significative if >1)

better score : 0 (non autistic) - worse score : the higher score is the worst

at 0, 12 months
Evolution of the Score ADOS-2 (Autism Diagnostic Observation Schedule 2) from baseline
Time Frame: at 0, 12 months

Clinical evaluation for autistic symptoms. Scale ranges :

  • A : Socialization : social interactions and communication : 0 to 20 (social interactions : 0 to 6 -communication : 0 to 14)
  • B : Restricted and repetitive interests : 0 to 8
  • Total : A+B : 0 to 28

Autism : total score>12 - Autism Spectrum Disorder : total score >8

Better score : 0 - Worse score : the highest score is the worst

at 0, 12 months
Evolution of the Score on Conners hyperactivity Scale
Time Frame: at 0, 6 months and 12 months

Clinical evolution for behavioral disorders and adaptive functioning

Conners Scale for Parents :

- Subscales : Behavioural difficulties (items 2-8-14-19-20-27-35-39) : 0 to 24 Learning difficulties (items 10-25-31-37) : 0 to 12 Somatisation (items 32-41-43-44) : 0 to 12 Impulsivity, hyperactivity (items 4-5-11-13): 0 to 12 Anxiety (items 12-16-24-47): 0 to 12

-Hyperactivity index : sum of the items (4-7-11-13-14-25-31-33-37-38) divided by 10 : 0 to 3

Conners Scale for teachers :

- Subscales : Behavioural difficulties (items 4-5-6-10-11-12-23-27) : 0 to 24 Impulsivity, hyperactivity (items 1-2-3-8-14-15-16) : 0 to 21 Inattention, passivity (items 7-9-18-20-21-22-26-28) : 0 to 24

-Hyperactivity index (sum of the items 1-5-7-8-10-11-14-15-21-26 divided by 10) : 0 to 3

Better score : 0 - Worse score : the highest score is the worst -Hyperactivity index : Significative if> 1,5

at 0, 6 months and 12 months
Evolution of the Score on ABC scale (Aberrant Behaviour Checklist)
Time Frame: at 0, 6 months and 12 months

Clinical evolution for behavioral disorders and adaptive functioning scale ranges :

  • Irritability : 0 to 45
  • Lethargy : 0 to 48
  • Stereotypy : 0 to 21
  • Hyperactivity : 0 to 48
  • Inappropriate speech : 0 to 12

Better score : 0 -Worse score : the highest score is the worst on each scale- there is no total score

at 0, 6 months and 12 months
Evolution of SAICAr levels in the urine
Time Frame: at 0, 6 months and 12 months
Evolution of the quantity of urinary metabolites from Baseline
at 0, 6 months and 12 months
Evolution of S-Ado levels in the urine
Time Frame: at 0, 6 months and 12 months
Evolution of the quantity of urinary metabolites from Baseline
at 0, 6 months and 12 months
Evolution of SAICAr levels in the blood
Time Frame: at 0, 6 months and 12 months
Evolution of the quantity of plasma metabolites from Baseline
at 0, 6 months and 12 months
Evolution of S-Ado levels in the blood
Time Frame: at 0, 6 months and 12 months
Evolution of the quantity of plasma metabolites from Baseline
at 0, 6 months and 12 months
Evolution of the number of seizures from Baseline for epileptic patients
Time Frame: at 0 and 12 months
at baseline, performing neurological examinations and interrogation
at 0 and 12 months
Evolution of antiepileptic treatments from Baseline for epileptic patients
Time Frame: at 0 and 12 months
at baseline, performing neurological examinations and interrogation
at 0 and 12 months
Evolution of electroencephalogram tracing from Baseline for epileptic patients
Time Frame: at 0 and 12 months
normal/abnormal
at 0 and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Pascale De Lonlay, MD, PhD, Assistance Publique - Hôpitaux de Paris
  • Study Director: Irène CEBALLOS-PICOT, MD, PhD, Assistance Publique - Hôpitaux de Paris
  • Study Director: Laurence ROBEL-GALLI, MD, Assistance Publique - Hôpitaux de Paris

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 14, 2019

Primary Completion (Actual)

June 17, 2022

Study Completion (Actual)

June 17, 2022

Study Registration Dates

First Submitted

August 13, 2018

First Submitted That Met QC Criteria

December 12, 2018

First Posted (Actual)

December 17, 2018

Study Record Updates

Last Update Posted (Actual)

October 12, 2022

Last Update Submitted That Met QC Criteria

October 10, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Adenylosuccinate Lyase Deficiency

Clinical Trials on Allopurinol

3
Subscribe